We propose to conduct the first comprehensive case-control study of carcinogen-metabolizing enzymes as biomarkers of susceptibility for cancers of the head and neck. The primary goal of the study is to elucidate gene-environment interactions in head and neck cancer by 1) comparing the frequency of at-risk genotypes for carcinogen metabolizing enzymes in head and neck cancer cases and matched controls and 2) to examine how environmental or lifestyle-related exposures are modulated by these genetic factors. The specific enzymes of interest include glutathione transferase mu, aryl hydrocarbon hydroxylase, debrisoquine hydroxylase, and N- nitrosodimethylamine demethylase. A total of 400 subjects (200 cases and 200 matched non-cancer controls) will be identified at the University of North Carolina Hospitals in Chapel Hill during a two year accrual period. The final sample will also include a subgroup of 74 black cases and controls. Cases will include newly diagnosed patients with pathologically- confirmed squamous cell carcinoma of the head and neck (oral cavity, pharynx, and larynx). Controls will include patients newly diagnosed with chronic sinusitis that requires surgery and will be matched with cases on race, age sex, and date of diagnosis. A blood sample will be obtained and an in-person interview conducted with study subjects. The interview will focus on lifetime smoking, alcohol, and dietary histories. The genotype for the enzymes of interest will be determined using PCR techniques applied to DNA obtained from the case and control blood samples. Cancers of the head and neck provide an excellent tumor system in which to apply and validate the independent and interactive effects of carcinogen exposures and genetic susceptibility factors since the established risk factors, tobacco and alcohol, are substrates for the enzyme markers evaluated in this study. This study can provide important new insights into the application of markers of genetic susceptibility, as measured by carcinogen metabolizing enzymes, in the etiology of cancer.